PL89072B1 - - Google Patents

Description

Patent description published: 30.12.1977 89072 MKP C07d 99/16 Int. Cl.2 C07D 499/48 READING ROOM Inventor:\ Patent holder: Bayer Aktiengesellschaft, Leverkusen (Federal Republic of Germany) the development of new penicillins which can be used as medicinal agents in medicine, such as medicinal agents for birds and mammals, as feed additives and ointments as growth promoters for animals. The new synthetic compounds are particularly suitable as medicinal agents for birds and mammals. and for humans in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, and especially by enteriobacteri and pseudomonads. These compounds can be administered orally or parenterally. Bactericides, such as ampicillin, are known from Sit. United Am. No. 2,958,648, have been shown to be very effective in the treatment of infections caused by Gram-idodia and Gnam-negative bacteria. However, they are not suitable for combating infections caused, for example, by bacteria of the Klebsiella Aerobaoter group or the indiol-positive Rroteus strains. Am. No. 3,142,673 and No. 3,282,926 are effective in humans against Klebsiella Aerobacter infection only when administered and continuously at high doses which can only be achieved by infusion. penicillanates are described in US Patent No. 3,483,188 and German Patent Laid-open No. 19,920, but none of the 6-(alpha-ldii) acids described and claimed in these patents The di-ureidium acetamides do not have an acyl group on the nitrogen atom in position 5 and the diureidium group. an alkoxy or amyoamino group with 1 to 4 carbon atoms, or a furyl group, X 1 is CO or SO 2 and B is an itienyl group or a group of formula V wherein R 7 , R 8 and R 9 are hydrogen, halogen and/or alkyl containing 1-5 carbon altomers and their salts, these compounds being due to the dissymmetry center, Cx can occur in both possible R and S configurations and as mixtures of the diastereamers resulting from them, consisting in the fact that the 6-aminopenicillanic acid of the formula 2 is reacted with the possibly formed reaction product in situ a compound of general formula 3 wherein Ri, X and B are as defined above and a compound of general formula 4 wherein R and R13 are the same or different alkyl groups having 1-5 carbon atoms and W is a halogen atom, in which in the presence of a base at -70°C to +50°C and the resulting penicillins are optionally carried out in salt. of the formula IV is carried out in a solvent containing the required amount of water and the pH is about 2-9, preferably 2-3 or 6.5-8.5. In the reaction according to the invention, the 6-nanopenicillanic acid of the formula II is preferably used in the form of a salt solution with the acid or is present. As a dispersant, for example, vitamin D is used, or a mixture of water with water-miscible organic athosolvents such as tetrahydrofuirane, dioxane, acetonitrile, isopropanol, acetate, dimethylformamide, dimethyl sulfiodine, or Jowas hexamethyltriamide, phosphomic. for example, hydrochloric acid, imamillium, and phosphoric acid. To convert nardinopenicillaic acid into a soluble salt with one of the above-mentioned solvents, for example, organic bases (such as sodium carbonate, sodium hydroxide, sodium bicarbonate, the corresponding potassium and calcium compounds, calcium oxide, magnesium oxide, miagmesium carbonate or buffer mixtures, and organic bases such as #vinyllandline, pyridine, yttriethylamine. For the preparation of a solution of 6-aminopenticillanic acid in anhydrous st It is used as a solvent, especially chloro-farm or diicoromethane, and as a base for the preparation of salts, for example, yttriethylamine, diethylamine, N-ethylpiperidine, N-ethylmorpholine and pyridine. (dissolved. Both may be present in part in the form of a suspension. The amount of base used in the reaction of the present invention may, for example, be determined by maintaining a certain waft and pH. In the event that the pH value is not measured and adjusted, or if this is not possible due to the lack of sufficient water in the solution, then in the case of the presence of 6-aminopenicillanic acid and anhydrous reaction medium, about 1.5-2.5 the molar equation of the rule. Also, the amount of silaged acid in a reaction according to the invention may, for example, be determined by maintaining a specific pH value or pH range. Reactions according to the invention are preferably carried out at as low a temperature as possible. The purer products obtained then improve the yield and protect the optical activity of the C* quinine from creemization. The limits of lowering the temperature, however, are determined by the lower solubility of the reaction components, which is not only limited to the lower elementpenattunes, or, alternatively, by the crystallization of the solvent which begins. The values given in the examples may, as in most chemical reactions, be lowered or increased, however, if the values given therein are significantly exceeded, side reactions reducing the yield and negatively affecting the purity of the product should be taken into account. In the reaction of acids of general formula 3 with compounds of general formula 4, preferably equimolar amounts of components are used in the reaction of acids of general formula 5 with a compound of formula 4. reaction. However, smaller or larger n an excess of one of the reaction components may have a beneficial effect on the purity of the product or on the yield. Work-up of the reaction mixture to obtain the penicillins of the formula I and their salts is carried out as follows (generally used for penicillins). The compounds of formula II are prepared in a known manner by the cleavage of penicillins G by fermentation processes or by chemical cleavage (Dutch Patent No. 67/13,809 and German Laid-open No. 2,062,925). The carboxylic acids of the general formula III are prepared in a known manner from amino acids. The preparation of the compounds of the general formula IV is described in the literature (J. med. 1963), pp. 2681; Tetrahedron 17, (1972), p. 114). As the non-toxic, pharmaceutically acceptable salts of the penicillins of formula I listed above, there are mentioned salts of the acidic carboxyl group such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts, and non-toxic substituted ammonium salts with amines such as lower di- and trialtholamines, procaine, dibenzylamine, N,N,-α-ubenzylethylenediamine, N-benzyyl-β-phenyl-ethylamphine, N-methylyl- and N-ethylmorpholine, 1-epheniamine, dehydrobiethylamine, N, N′-Hbis-dehydroamethylethylethyldiamine, lower N-alkniopiperidines and other amines that can be used to form salts with penicillins.Chemotherapeutic effects of new pencillins tested in vivo and in vitro. In vitro inhibitory values (MHK-minimaine the inhibitory concentration - see tablea) was determined in the liquid medium by serial tube dilution test, reading after a 24-hour incubation period at 37° C. The MHK value is determined in a series when dispersed through a test tube in which no suspension was observed. The following medium was used as the medium: 10 g Lab Lemoe in 10 g peptone dextrose (MERCK) and 1000 ml pH 7.4 buffer. The spectrum of activity includes both Gram-negative and Gonam-positive bacteria. A particular advantage of the penicillins of the invention is that they are active both in vitro and in animal experiments against ampicillin- and carbenicillin-resistant bacteria of the Klebsoellia-Aerebaciter group, against ampicillin- and carbenicillin-resistant bacteria. 072 6 mdol-positive Ptrateus ii ProvMencia, against ampicillin- and carbenicillin-resistant strains of Escherichia doli, against carbandcillin-resistant Plseudemenas aerugdinosa and Sernatia matrcescens. In general, an excellent effect is obtained with a single as well as repeated subdiavand. The penicillins of the formula I are stable to gastric acids. In particular, some new penicillins are well tolerated by the organism, and this is particularly evident when maximally high doses are injected intravenously into the tail vein of mice, and mice tolerate these complications as well. ml for individual penicillins of the formula 1 in relation to and against a range of bacteria. This table shows the superiority of the penicillins of the formula I in comparison with the commercial ampicillin in terms of activity against Gram-negative bacteria. The numbers assigned to the individual penicillins correspond to the numbers of the examples in which the preparation of these penicillins is described. For oral administration, they are used in the form of tablets, for example additionally containing starches, lactose, certain grades of alumina, etc., or in the form of capsules, drops or granules, alone or in combination with the foregoing or equivalent carriers. They may also be administered orally in the form of elixirs or suspensions containing the flavorings or dyes customary for this purpose. In the case of parenteral administration, a sterile solution is preferably used, optionally containing other ingredients such as sodium chloride or glucose, to provide an intranasal solution. Penicillins in the form of dry ampoules are preferably used to prepare such solutions. For oral and parenteral administration, daily doses of 000-1,000,000 E/kg of body weight are preferably employed. E stands for units where 1 mole of penicillin contains 5.95.14 X108E. This amount may be administered as a single dose or in the form of a drip or also in smaller doses. For topical application, penicillins may be prepared in the form of ointments or powders. The following examples further illustrate the invention without limiting its scope. 1 2 3 4 6 7 8 9 11 13 18 19 ampicillin 14 <0.8 <1 <1 1 1.6 256 8 4 2 2 128 <1 4 1 4 4 0.8 E. coli A 261 200 256 256 200 256 512 512 512 512 512 512 256 256 256 256 400 C165 3.1 4 4 12.5 256 32 16 8 8 512 4 8 8 8 8 6 183/ /58 1.6 4 4 6.2 256 16 8 8 256 2 4 16 16 8 200 Genus Proteus Vulg. 1017 3.1 8 4 12.5 256 32 32 16 8 256 4 16 4 32 8 400 Mórg. Psdm.F41 50 128 64 200 256 256 128 128 64 512 64 128 256 64 64 aerug. Walter 50 64 64 200 256 128 64 64 64 512 64 128 256 64 32 200 50 256 128 32 32 32 512 16 32 32 32 32 100-200 63 12.5 128 256 100 256 256 128 128 128 512 16 64 32 4 32 100-200 1 Staph.aure-U9 1756 400 64 128 200 256 128 64 -64 64 512 128 256 64 128 . 64 133 <0.8 <1 <1 <0.8 4 2 <1 <1 2 16 2 4 1 <1 <1 <1 <1 Strept faec.ATCC 9790 12.5 64 32 100 256 128 64 64 64 512 64 128 32 32 16 12.5 blica Type JS [org. 932 8 16 - 32 64 16 32 8 56 16 28 1 4 32 (Psdm. F41 50 128 64 200 256 256 128 128 64 512 64 128 256 64 64 aerug bacteria. Walter 4 550 64 62 64 200 64 128 256 64 32 200 l 1 Klebsiella KIO 1 6.2 32 16 50 256 128 32 32 32 512 16 32 32 32 32 100-200 63 12.5 128 256 100 256 256 128 128 128 512 16 64 32 4 32 100 -200 1 Staph.aure- U9 1756 E 400 64 128 200 256 128 64 -64 64 512 128 256 64 128 .64 133 <0.8 <1 <1 <0.8 4 2 <1 <1 2 16 2 4 1 <1 <1 <1 <1 Strept faec.ATCC 9790 12.5 64 32 100 256 128 64 64 1 64 f 512 64 128 32 32 16 12.5 60 65 The β-lactam content of penicillin was determined iodinetrically. here the substances showed an infrared spectrum corresponding to their structure.The study of the nuclear magnetic resonance (NMR) spectrum of penicillin was carried out in a CD3OD solution.The signals given in the examples correspond to the t scale.They correspond to the structure of each compound. org. 932 8 16 32 t 64 16 32 8 DO 16 Zo 1 1 4 32 60 ? I D II { 65- I89 The accuracy of the analysis was taken into account and the water content of the penicilline. D-α-[/3H-Methylsulfionylin-Tidazolidin-2-one-1-yl]-carmiamino]-phenylacetic acid is dissolved and in 40 parts by volume of methylene chloride with the addition of a small amount of tetrahydrofuran, cooled to -40° C and with vigorous stirring add 2.0 parts by weight of N-methylmorpholine. Then, with vigorous stirring, a solution of 3.75 parts by weight of tetramethylene chloride in 15 parts by volume of methylene chloride, cooled to -40°C, is added, allowed to stand for 5 minutes at -40°C, and combined. then with a solution, cooled to 0°C and adjusted to pH 2.5, of 4.7 parts by weight of 6-amiinopenicillanic acid in 80% by volume of aqueous tetrahydrofuran. Additional portions of N-methylmorpholine are added to maintain the value The pH of the mixture is 2.5. It is stirred for 30 minutes without refrigeration, keeping the pH value at 2.5. Then 40 parts by volume of water are added, the pfl value is set to 7, the methylene chloride and tetrahydrofupan are removed on a rotary evaporator, the solution is extracted once with 50 parts by volume of ethyl acetate and the aqueous phase is covered with fresh ethyl acetate. With stirring and cooling with ice, it is acidified to a pH of 1.5 and with dilute hydrochloric acid, the ethyl acetate is separated off, the aqueous phase is extracted twice more with ethyl acetate, the combined organic phases are washed with water and dried over MgSO 4 . Then it is filtered, treated with 20 parts of a molar solution of sodium salt of 2-ylhexanoic acid in methanol-containing ether, evaporated under reduced pressure to almost dryness, the residue dissolved in methanol and precipitated penicillin sodium salt by adding 10 times the amount of absolute ether. The product is filtered off, washed thoroughly with absolute ether and dried over P 2 O 5 in a vacuum desiccator to give a yield of 84% with 74% of p-flatetam. 4.8 N 11.3 S 10.4 Marked: 43.4 5.4 11.3 10.3 IR Spectrum: bands at 3325, 3055, 30B5, 3002, 2965, 2924, 2865, 177il, 1738 , 1679, 1610, 15E9, 1398 and 11711 cmi P NMR signals t = 2.3 - 2.8 (5H), 4.4 <7H), 4;5 <2H), 5.8 (1H), 6 .16 (4H), 8.4 (3H) and 8.5 ppm (3H). B 1) D-α-[(3-methylsulfonyl-imidazolin-2-one--yl)-carbonylamimo]-phenylacetic acid of the formula 7. 16.6 parts by weight of (D-(-C-phenylglycine) are dissolved in 150 parts by volume of a 50% aqueous solution of dioxane with the addition of a sufficient amount of 2N stock hydroxide solution. The pH of the solution is adjusted to 7.5 with 2N hydrochloric acid, whereby the amino acid is partially isolated in finely divided form. While cooling with ice, 12(Moirak, ar1,2,1,2,2,2,2 m2) are introduced in portions and the pH value is maintained at 7.5 by the simultaneous addition of 2 N sodium hydroxide solution. The mixture is stirred without cooling until the pH value, without addition of sodium hydroxide solution, begins to change. maintaining the oa level at 7.5, which takes about 10 minutes. Then, 50 parts by volume of water are added, concentrated on a rotary evaporator to half of the original volume and extracted once with 50 parts by volume of ethyl acetate, after filtering off the unreacted C Then, it is acidified to pH 2, extracted several times with ethyl acetate, the combined organic phases are washed with water, dried with MgSO 4 , filtered, evaporated to dryness and recrystallized from acetone/initromethane, obtaining a product at melting point 250° C. Yield 56%/© Analysis: Found: C 45.7 H 4.4 N 1-2.3 S 9.4, found: 45.7 4.5 12.3 9.2 Nujol infrared spectrum: bands at 3345, 3600, 2300, 1731, 1652, 1538, 1210 and 1168 cm-1.S NMR signals at % = 1.2 (1H), 2.55 (5H), 4.6 (1H), 6.2 (4H) and 6.6 ppm (3H). 2) D,L-α-[(3-Methyylsulphinyyl)amididazolidin-2-Hon-1-yl)carbonyl alkyl] acid of the formula 8. This acid is prepared as described in Example 1B1 from 5.8 parts by weight of 4-chloro- 1.6 H 3 1.6 H 3 .7 Cl 9.4 N 11.2 S 8.5; determined: 40.8 3.7 9.2 11.1 8.9. Nujol infrared spectrum: bands at 3700-2200, 3310, 1730, 1654, 1540 and 1168 cm -1. NMR signals at t = 1.1 (1H), 2.55 (4H), 4.5 (1, H), 6.1 (4H) L and 6.65 ppm (3H). The 2-acetic acid of the formula 9. Prepared as described in Example 1B1 from 5.5 parts by weight of α-phenyl-2-glycim and 6.8 parts by weight of 1H-morocarbonyl-3-n-methylsulfonyl-2-imidazolidine, yield 88°. 100% and the melting point of the crude product is about 110°C. Analysis: Calcd: C, 38.0; H, 3.8; N, 12.1; S, 18.4; Nujol infrared spectrum: bands at 3600-2200, 3315, 1740, 1725, 1664, 1525 and 1170 cm"1. NMR signals pz t = 1.2 (1H), 2.4-3.1 (3H), .2 (1H), 6.07 (4H) and 6.67 ppm (3H). M 4) L-α-[/3H-methylsulf6hy acid! ^^ ^co1-1-yib/^arbcmylamimio]-phenylacetic acid of formula . This acid is prepared as described in Example 1B1 from 5.3 parts by weight of (L+/-C-phenylglycine) and 6.8 parts by weight of 1 HcMorocarbonyl-3H-methyl]sulphines (1 M). C. Amaliza: Calculated: C 45.7 H 4.4 N 12.3 S 9.4, Designated: 449 4.5 11.9 9.4 65 The infrared and magnetic ireso-8&072 nuclear narlisph spectra are identical to the product of Example 1BI.) D,L-αE(3H-methyl)ulifamino]-non-1-yl)-carbonyl aimino]-2,6-diethyltertioenylacetic acid of formula 11. This acid (prepared as described in Example 1B1 with 7.7 parts by weight of 26-dichloro-G-phenylyl lykyin and 6.8 parts by weight of 1-chlorocarbonyl-3-methylsilane-2, the melting point of the product being 10,260°C. and an efficiency of 60%. at t = 0.9 (1H, 2.4-2.65 (3H), 3.4 (1H), 5.8-6.2 (4H) and 6.65 ppm (3H). 6) acid II- α-[/3-NaoethylD-Bimidase(alidin-2-ori-1-yl)(4-carbonylamino]-phenyloate of formula 12. This acid is prepared as described in Example 1B1 from 5% of the hydrogen (L+/-C) ^-phenylglycine and 5.7 parts by weight of 1-bonyl-3-acetyl-imidiaztoylidone-2. The melting point of the product is 214°C and the yield is 69%. Anidizia: Calcd: C, 55.0; H, 4.9; N, 13.8; resolved: 53.5 5.2 13.7. Infrared spectrum in nujol: bands at 3650^2250, 3300, 1735, 1665 and 125(2cni-1). NMR signals at t = 1.0 (1H), 2.3^2.8 (5H), 4.5 ( 1H), 6.2 (4H) and 7.6 ppm (3H). 13. The rbene acid was prepared as described in Example 1B1 from 6.2 parts by weight of D,L-4-chloro-C-phenylglycine and 5.7 parts by weight of 1-chlorocarbonyl-3-hydroxyphenylglycine (azolidarylene). 2. The melting point of the product is 194°C and the yield is 53V. 12.2 Nujol infrared bands at 3700-2300, 3290, 1725, 1686, 1648 and 1252 cm -1. NMR signals at t = 0.9 (1H), 2.55 (4H), 4.45 ( 1H), 6.2 (4H) and 7.55 ppm (3H). 14. This acid is prepared as described in Example 1B1 from 5.4 parts by weight of 4-methyl-C-phenylglycemic acid and 5.7 parts by weight of and by weight of 1-chlorocarbonyl-3-acetylim:idiaziolidione-2, with a yield of 420%. Infrared bands in nujol at 3600-2200, 3310, 1738, 1712, 1678, 1666 and 1256 -1. NMR signals in acetone d6 at t = 1.0 (1H), 55 2.6 (2H), 2.8 (2H), 4.5 (1H), 6.2 (4H), 7.6 (3H) and 7 .7 ppm (3H). 9) D,L-α-[(3H-Acetylimidphazolididin-2-one-1-yl)caribonylamino]-α-thienyl-2-acetic acid of formula 15. This acid is prepared as described in Example 1B1 from 8.6 parts by weight of itienyl-2-anoic acid and 9.5 parts by weight of 1-chloridearbonyl-3-iaceitylimimide:aEolidone-2. The melting point of the product is 197°C and the yield is 62%. 40 65 Anadizate calcd: C 46.3, H 4.2, N 13.5, S 10.3; amazono: 47.1, 4.4, 13.8, 9.7. Infrared bands in niujol at 3280, 3080, 3450-2300, 1728, 1680, 1652; 15E2, 1260 and 705 ohm"1. NMR signals at x = 1.1 (1H), 2.5-3.2 (3H), 4.2 (1H), 6.2 (4H) and 7.6 ppm (3H)) D,L-[alpha]-[(3-aO-ethyl-imidazolidin-2-one-1-yl)-carfoonylamino]-2,1)-dimethyl acid of formula 16: Theine acid is prepared as described in Example 1B1 from 6.7 parts by weight of 2,6-dichloro-C-phenylaglycine and 5.3 parts by weight of 1-chlorocarbonyl-3-acetylimidase-2-done, melting point 250°C, yield 74%. Analysis: Calcd: C, 44.9, H, 3.5, Cl, 19.0, N, 11.2, determined: 45.2, 3.1, 18.5, 11.4 Infrared and Nujol Priza 3600 bands -2200, 3302,' 1735, 1682, 1625, 1520 and 1255 ohms. NMR signals at t = 0.7 (1H), 2.3-2.7 (3H), 3.4 (1H), 6 .2 (4H) and 7.6 ppm '{3[mu]).' C. 1-Chiocarbdate-3-methylisulionylmdazolidone-2 of formula 17. 16.4 parts by weight of 1-methylsulfanylquinidazolidione-2-one is boiled with 27 parts by weight of trimethylchlorosilicate and 20 parts by weight of triethylamine in dioxin environment within 3 days. The precipitated triethylamine hydrochloride is filtered off, treated with 11 parts by weight of phosgene and left to stand overnight at room temperature. It is then evaporated to dryness and recrystallized from boiling acetone. The product is obtained, mp 178°C, yield 70%. Analysis: Calcd: C 26.5, H 3.1, Cl 15.7, OST 12.4 S 14.1, labeled 27.2, 3.4, 15.3, 12.4, 14.1 NMR signals at t = 5.6-6.2 (4H) and 6.6 ppm (3H) Infrared bands at 3010, 1807, 1721, 1360, 1165, 984 and 742 cm-i. Such an Islamic product can also be obtained from 1-methylsulfonylimidazolidinium-2 and an excess of phosgene in methylene chloride in the presence of pyridine.D.N- 2-methylsulfonyl-imidazolidone of the formula 18. 1) To a suspension of 43 parts by weight of 2-methylsulfonyl-imidazolidone in 400 parts by volume of dry tetradarofuran, 63 parts by weight of methanesulphochioide is added dropwise at room temperature and stirred for 1 hour at -40°C. and then heated under reflux for 1 hour. The solvent is then distilled off under reduced pressure and kept for 1 hour at 60°C under an oil pump. The residue is recrystallized from warm acetone. The product is obtained, mp 193°C, yield 25%. Analysis: Calcd: C 29.3, H 4.9, N 17.1, S 19.5, Determined: 29.4, 5.0, 17.2, 19.6 Infrared bands at 3250, 3115, 1715, 1350 and 1160 ohm-i NMR signals at t = 2.4 (1H), 6.2 (2H), 6.5 (2H) and 6.8 ppm (3H) 2) Suspend 43 parts by weight 2-imidiaziolidoane in 300 parts by volume of dry tetrahydrofuran is added dropwise over the course of 30 minutes, with stirring, 80 parts by weight of methanesulfochloride and then 56 parts by weight of triethylamine so that the internal temperature is 35-40°C. For 2 hours at 45°C, remove the solvent under reduced pressure, extract the residue twice with 150 parts by volume of chloroform, and recrystallise the obtained methanol crystals. The product is obtained in a yield of 49%. The product, according to its melting point and infrared spectrum, corresponds to the above-described N-methylsulfonylimiidiaziolidol-2. Example 2. D,L-[alpha][(3-methyl&ulfonyl)imidazolidin-2-one-1-yl}-carbanylamino]-4-morobenzylpenicilliin sodium salt of the formula 19. This penicillin is prepared in the manner described in Example 1A with 7.5 parts by weight of D,L-α-1[(3-Methylsulfonylamino)-carbonylamino]-4H-chlorophenes. 3.75 parts by weight of tetramethylchloroformamidinium chloride and 4.7 parts by weight of 6-aminopenicillanic acid. Instead of N-methylnorpholine, 2.02 parts by weight of triethylamine are used. A product is obtained in 65% yield with a β-lactam content of 62%. According to the NMR spectrum, the product still contains 24% of methylsulfonylamidazolidoneslaccarbonylaminochlorophenylic acid which can be removed by fractional acidification of aqueous sodium penicillin. Nujol infrared bands at 3310, 1760, 1722, 1670, 1705 NMR at r = 2.53 (2H), 2.67 (2H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.1 (4H), 6.65 ( 3H), 8.3-8.5 ppm (6H) (in d4 methanol). Example III. D,L-[alpha]-[(3-Methylsulfonyl-imidazoli-Min-2-an-1-yl)-carbonylamino]-a-thienyl-2-methylpenicillin sodium salt of formula 20. These penicillins are prepared as described in Example 1A of 7. 0 parts by weight of D,L-[alpha]-[(3-methylsulfonyl)]idazolidin-2-(an-1-yl)-[alpha]-carbonylanino]-[alpha]-thienyl-2-acetic acid, 3.75 parts by weight of methyl teiromethyl chloroform chloride; amiidinium and 4.8 parts by weight of 6-narrinopenicicillanic acid, yielding a product with a yield of 38% with a β-lactam content of 68%. NMR signals at % = 2.5-3.1 <3H), 4.1-4.6 (3H), .8 (1H), 6.1 (4H), 6.7 (3H) and 8 .25-8.5 ppm (6H) The crude product still contains about 30% D,L-α-[(3-methylsulfonyl)dimidazolidin-2-an-1-yl)-carbanylamino]-α-thienyl-2-ootane sodium salt, which can be removed by fractional acidification of the aqueous solution. of the formula 21. Penicillin Example 1A with 6.8 parts by weight of L-α-[(3-methylsulfonylimidazolidin-2-one-α-yl)-carbonylaminio]-phenylactic acid, 3.75 parts by weight of tetramethylchloroformamidinium chloride and 4.7 parts by weight of 6-aminopenylcylanic acid. The yield is 72% and the β-iatotam content is 66%. Analysis: Calcd: C 44.1, H 4.7, N 11.5, S 10.6; determined: 53.5, 5.5, 11.5, 10.1. When calculating the data for analysis, a water content of 3% and a content of 2-ethylhexanoic acid sodium salt of 2% were taken into account. w Infrared bands at 3310, 1760, 1722, 16G5, 1602 and 1168 cm -1. NMR signals at t = 2.6 (5H), 4.35^1.8 (3H), .8 (1H), 6 .2 (4H), 6.7 (3H) and 8.4 ppm (6H). -2,6H-dichlorobenzylipenic3n-Lines of formula 22. These penicillins are prepared as described in Example 1A from 7.0 parts by weight of D,L-[alpha]-[(3-methylsulfonyl)imidiazoilidin-2HO(n-1-yl)-26-toarbonylamino]-2 acid, 6-dichlorophenylacetic acid, 3.2 parts by weight of tetramethylchloroformamidinium chloride, and 4.3 parts by weight of 6-aminopenicillanic acid The reaction of the substituted phenylacetic acid with tetramethylchloroformamidinium chloride is, however, at -20°C. This is described in Example 1A at -40° C. Yield 77%, β-lactam content 61.5%. Analysis: Calcd: C 38.5, H 4.0, Cl 12.2, N 10.0, S 8.7, marked: 36.0, 4.0, 12.6, 10.5, 9.3 Infrared bands at 33 10, 1764, 1720, 1678, 1607, 1512, 1255 and 1167 cm"i (in nujol). NMR signals at t = 2.5-2.9 (3H), 3.8 (1H), 4.45 (2H), 5.8 (1H), 6.15 (4H), 6.7 (3H) and 8.3-8.6 ppm (6H). When calculating the values for the analysis, the content of penicillin 62%, sodium isolate of α-[/3-methylsulfanylaminddazolidin-2Hon-1-yl]-icarbylamic acid was taken into account! n.o.]-2,6-dichlorophenylacetic acid 40 30%, sodium 2-ethylhexanoic acid 4.0% and 3.6% water. These contents result from the NMR spectrum of the crude product. By fractional acidification of an aqueous solution of the crude product, penicillin can be obtained in pure form. 45 Example VI. A. L-[(3-Acetyl-ImidazoMyn-2-ian-1-yl)-arbonylamino]-ibenzyl-penicillin sodium salt of formula 23. These penicillins are prepared as described in Example 1A with 5.0 parts by weight 50 L-α-[(3-Haio-ethylimidazoilidin-2-one-1-yl)-phenylamino]-phenyl acetic acid, 3.1 parts by weight of tetramethylchlorophyllamidinium chloride and 4.3 parts by weight of 6-aminpenicillanic acid. The yield is 74% and the 3-lactam content is 75%. Infrared bands in nujiol at 3305, 1765, 1730, 1675, 1605, 1520 and 1258 ohms. .8 (5H), 4.5-^1.8 (3H), .8 (1H), 6.22 (4H), 7.5 (3H) and 8.4 ppm (6H) B. Chloride 3 -Acetylimidazolin-2-ion-1-carbanyl of the formula 24. Parts by weight of N-acetylaminidazolidone--2 are added to a mixture of 25 parts by weight of triethylamine and 150 parts by volume of dry benzene, and added dropwise over the course of 65 minutes. 27 parts by weight of trimethylamine in 40 parts by volume of benzene at room temperature with stirring, the mixture is then boiled for 18 hours under reflux, and the precipitated itriethylamine hydrochloride (22 parts by weight) is filtered off after cooling. = 100%) and thoroughly washed with dry benzene. To the benzene solution thus obtained, at 5°C, a solution of 17 parts by weight of phosgernium in 50 parts by volume is introduced nzene and left overnight at 5°C. The burner is then removed under reduced pressure and the residue is dried under an oil pump. The product is recrystallized from a mixture of acetone and penitaine. The yield is 81% and the melting point is 104°C. Analysis: rolled: C 37.7, H 3.7, Cl 18.6, N 14.7; reduced: 39.3, 4.3, 17.7, 14.7. Subreddened bands at 1798, 1740, 1690 and 1660 cm-1. NMR signals at t = 5.65^6.3 (4D) and 7.45 ppm (3H). According to the NMR spectrum, the product still contains -10% of N-acetic mimidineolone, which, however, does not prevent the reaction with C-phenylglycine and other amino acids (Example 1B 6). C. N-Phacetyl imidazolidone-2 of the formula 25. To a suspension of 25.8 parts by weight of thiidazolidone-2 in 350 parts by volume of dry tetrafavodarofuanane, add 23.6 parts by weight of acetyl chloride in 100 parts by volume at 0°C for 60 minutes. tetradomotfurian. It is then stirred for 3 hours at room temperature, then dry air is blown through the solution for some time, the solvent is removed under reduced pressure and the residue is crystallized from boiling nitamethane. Yield: 52%, temp.: mp 188°C. Analysis: Calcd: C 46.9, H 6.9, N 21.9; found: 47.4, 6.2, 22.5. Infrared bands at 3230, 1730 and 1640 ohms. 1. NMR signals at t = 6.2 (2H), 6.5 (2H) and 7.6 ppm (3H). Example 7. D,L-sodium salt -[(3-'Acetyl-thaidazoilidin-2-ion-1-yl)-carbonylamino]-4-ichilioiro-benzylpenicillins of formula 26. These penicillins are prepared as described in Example 1A from 4.0 parts by weight of acid D, L-α-[(3-Acetylimidazolidin-2-one-1-yl)-carbonylamino]-4-chlorophenylacetic acid, 2.2 parts by weight of tetramethylchloroformamidinium chloride and 3.25 parts by weight of 6-aminopenicillanic acid. 76% and O-lactam content 89%. Infrared bands in nujol at 3310, 1760, 1730, 1670, 1600, 1518 and 1259 cm-1. NMR signals at t = 2.4-2.9 (4H ), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.2 (4H), 7.5 (3H) and 8.3-8.6 ppm (6H). VIII. D,L.-a-[(3-Tacetyl-thaidazolidin-2-one-1-yl)-carbonylamimo]-4-methyl-sodium salt lbenzylpenicillins of formula 27. These penicillins are prepared as described in Example 1A from 3.2 parts by weight of D,L-a-[(3-acetylimidazolidin-2-one-1-yl)carbonylamino]-4-methylphenylacetic acid, 1.9 parts by weight of tetramethylchloroformamidinium chloride and 2.6 parts by weight of 6-aminopenicillanic acid. The yield is 45% and the β-lactam content is 83%. Infrared bands in nujol at 3305, 1760, 1725, 1672, 1600, 1515 and 1255 cm-1. NMR signals at t = 2.6-2.8 (4H), 4.4^-4.8 (3H) , 5.8 (1H), 6.2 (4H), 7.5 (3H), 7.7 (3H) and 8.3-8.6 ppm (6H) Example 9 D,L-a-sodium salt [(3H-AcetylthaidaEolidin-2-one-1-3to)-toartol-2-methylpenicillins of formula 28. These penicillins are prepared as described in Example 1A from 8 parts by weight of D,L-α-[[3-acetylimidazolidine] acid. 2-on-1-yl/-carbonylamino]-thienyl-2-acetic acid, 4.9 parts by weight of tetramethylchloroformamidinium chloride and 6.5 parts by weight of 6-aminopenicillanic acid. The yield is 88%, and the β-lactam content is 87% Infrared bands in inujol puza 3302, 1760, 1732, 1678, 1605, 1520,'1315 and 1261 cm-1. NMR signals at t = 2.5-3.2 (3H), 4.0^1.5 (3H), 5.8 (1H), 6.2 (4H), 7.5 (3H) and 8, 2-8.6 ppm (6H). EXAMPLE 10 Sodium salt of D,L-[alpha]-[[3-iacetylthaidazo]dyn-2-one-1-ylflo]-chlorobenzylpenicillin of formula 29. These penicillins are prepared as described in Example 1A with 6.5 parts by weight of D,L-a-[(3-Acetylimidazolidin-2-one-1-yl)carbonylamino]-2,6-dichlorophenylacetic acid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and 4.3 parts by weight of 6- aminopenicillanic acid, the reaction of the substituted phenylacetic acid with tetramethylchloroformamidinium chloride being carried out at -10°C. The yield is 29 and the β-lactam content is 66%. Infrared bands in nujol at 3310, 1765, 1735, 1685, 1615, 1520, 1265, 1100, 1028 and 805 cm -1. NMR signals at t = 2.7 (3H), 3.8 (1H), 4, 3-4.6 45 (2H), 5.8 (1H), 6.2 (4H), 7.5 (3H) and 8.2-8.6 ppm (6H) According to the NMR spectrum, the crude product will contain ¬ra 27% sodium salt of D,L-α-[(3-acetylimidazolidin-2-one-1-yl)carbonylamino]-2,6-dichlorophenylacetic acid, which can be removed from the product by fractional acidification Example 11 D-α-[(3-EthylsulfonylamidazoMdin-2-one-1-yl)-4-carb-mylamino]-ibenzylpendcylline sodium salt of formula 30. 2.9 parts by weight of D-α-[/3-acid ethylsulfonylimidazolidin-2-one-1-yl/-carbonylamino]-phenylacetic acid, containing 1 mole of isopropanol and 1 mole of water of crystallization, is dissolved in parts by volume of tetrahydrofuran.60 The solution is cooled to -30°C and combined with a solution of 1.6 parts by weight of tetramethylchloroformamidinium chloride in 30 parts of dichloromethane, cooled to -40°C e-tanu. The mixture is then brought to -25°C and 0.9 parts by weight of N-methylmorpholine is added and, after 3 minutes, cooled to -5°C. C. a mixture of 2.3 parts by weight of 6-aminopenicillanic acid and .25 parts by weight of a 90% aqueous tetrahydrofuran solution, the pH being adjusted to 2.5 with about 10% hydrochloric acid. the mixture until it reaches 0°C and maintains the pH at 3.5 by adding the appropriate amount of N-methylmorpholine or dilute sodium hydroxide solution. After 1 hour, addition of base to maintain pH 2.5 was no longer needed. The pH is then adjusted to 7, most of the tetrahydrofuran is removed in vacuo, the remaining aqueous phase is shaken once with ether, the ether phase is overcast and the layer of ether/acetic acid is acidified to 4 times pH 1.5. The organic phase is separated, washed with water and dried for 1 hour over MgSO 4 at 0°C. The desiccant is then removed and the penicillin sodium is precipitated with an ethereal methanol solution of 3-ethylp-hexanoic acid sodium. Yield 3.2 parts by weight, 3-lactam content 81.9%. NMR signals at t = 2.4-2.85 (5H), 4.4^1.8 (3IJ), 5.8 UH ), 6.15 (4H), 6.3-6.7 (2H) and 8.3-8.8 ppm (9H). D-α-[(3-Ethylsulfonylimidazolidin-2-one-1-yl)-carbylanine]-phenylacetic acid of formula 31. The tetrachloromethane reaction mixtures are introduced at about 09°C with 4.5 parts by weight of 3-ethylimidazolidin-2-one-1-carbenyl, the mixture is left for 4 hours at 20%, then the solvent is removed and the residue is thoroughly treated in a mortar with 1N H2O. The solid product is sucked, washed with water, dried and filtered from isolate. The yield is 0.0 parts by weight. The melting point is 102°C. makes the product solidify again and (tppindiejie w itempemajbuiree 211 ° C. Contents of 1 mole of isopropanol and 1 mole of water are included in the calculation of the values for analysis. Analysis: Calculated: C 47.1, H 6.3, N 9.7, S 7 .4, denominator: 4.7.1, 5.7, 9.7, 9.6 NMR signals at t = 2.6 (5H), 4.6 (1H), 6.1 (4H), 6 .3-6.7 (2H) and 8.5 -8.7 ppm (3U). α-Ethylsulfonylimidazplidin-2-one-1-carbonyl chloride of the formula 32. Prepared from 3-ethylsulfonylimidazolidin-2-one and phosgene in dichloromethane in the presence of pyridine at 20°C. Melting point 174° C. Analysis: Calcd: C, 29.9, H, 3.8, Cl, 14.8, N, 11.6, 13.3; marked: 30.1, 3.8, 14.7, 11.8, 13.3. NMR signals at t = 5.5-6.1 (403, 6.2-6.65 -(2H) and 8.4-8.75 ppm (3H). 1-Ethylsulfonylimidazolidin-2-one of formula 33. This compound is obtained by heating equimolar amounts of imidazolidinone-2 and ethylsulfonyl chloride at 200 210 ˚C (until H<31 is complete). and ethyl acetate from the crude product and recrystallization from acetone with the addition of activated carbon, mp 114%, Analysis: Calcd: C, 33.7, H, 5.7, *N, 15.7, S, 18.0; 33.1, 5.7, 16.3, 17.7. NMR signals at t = 6.9-^6.7(4H) and 8.5-[Delta]Z ppm (3H). Example XII. Sodium D-α-[(3-ylsulfonyl-imidazolidin)-2-one-1-yl)-carbonylamino]-b-isylpenicillin of formula 34. A solution of 8.6 wt. The solvent is cooled to 0°C, then a solution of 7.0 parts by weight of 3-ethylsolfonylyl inidazolidin-2hoin-1-carboinyl in 15 parts by weight of divinyl alcohol is added to it with further cooling, followed by a mixture the temperature is kept overnight at 0° C. Next, 5.0 parts by weight of irateiromeyl chloride are added in 15 volumetric batches of two oxygen methanes and the mixture is left to stand for 1 hour at room temperature. At a temperature of 0°C, the mixture of this substance is adjusted to pH 2.5 with dilute hydrochloric acid, we suspend 8.2 parts by weight of the 6:*aminopenicilliferic acid in 85 parts by volume with 80% of the monohydrogen solution and maintain the value c pH 2.5 by appropriate addition of diluted NaOH. The mixture is then stirred at 0° C. for a further 1 hour and, if necessary by further addition of diluted NiaOH, the pH is maintained at 2.5. The pH is then adjusted to 7.0, the volatile origanine is removed under reduced pressure, and the penicillin sodium is isolated as described and in the following example. The yield is 8.0 parts by weight and the avitacity of the β-lactic acid is 58%. 45 Example XIII. .alpha.-[(3-Ethylsulphinyl}imdiisollidin-2-one-1-yl}-carb-donyl}mino]Hp-cmorobylpeinicine sodium salt, Gap 35. These penicillins are prepared as described in Example 11 of 4 5 parts by weight of α-[(3-neethylsulfon]onyl^nylaniino]-p-chlorophene, 2.3 parts by weight of tetramethylolyl chloride, 1.3 parts by weight of N-methylmorpholine and 3.2 parts by weight of 6-nam]inopenicillanic acid - 55%, with ipzyin the combination with 6-(amimopenicillanic acid) is carried out after 6, iminutes. The yield is 4.4 parts by weight. Infrared bands in inujoiu ipray 3300, 1765, 1725, 1670, 16p0, 1500-1520, 1260, 1165, 1130 cmi. 60 .alpha.-[(3-Ethyl)phonylthodazole]carbonylanoinol-p-chlorophenyl aioic acid, Formula 36. For a slurry of 11.0 parts by weight of p-chlorophenylene acid in 110 parts by volume of 50% aq. DiotoaaMi 65 adds the amount of distilled sodium hydroxide needed17 to dissolve the acid. Next, dilute hydrochloric acid is added to pH 7.5-8.0. 3-Ethylsultonylimmazolidin-2-one-1-toarbanylium chloride is then added portionwise at about 0°C and the pH of the mixture is maintained at 7°C with dilute sodium hydroxide solution. Stirring is then continued until addition of sodium hydroxide solution is required to maintain the pH value between 7.5 and 8.0. The ploteim at pH 6.5 removes the main (the amount of dioxane under reduced pressure, adds about 200 volumes of water, at pH 9.0 extracts once with ether and discards the ether extract, covers with a layer of fresh ether and drains the pH, stirring, to 0.5 The organic layer is then separated, washed, dried and completely evaporated under reduced pressure. Yield 4.9 parts by weight, melting point 1168° C. NMR signals at r = 2.6 (4H), 4.6 (1H), 6.1 (4H), 6.3-6 .7 (2H) and 8.4r-8.8 ppm (3H) Nujol infrared bands at 3300, 1720, 1650, 1540, 1350, 1160 cm.sup.1 Example 14. Proceeding as described in Example IA and introducing 0.02 moles of the following compounds to the reaction: D-a-[(3-methylsulfonyldimdazolidin-2-one-1-yl)-carbonylamino]-4-chlorophenylacetic acid, D-a -[/3-Methylsylphenylphenyl]-yl/-carbonylamino]-4-methylphenylox-oic acid, D-α-[/3-methylsylphinylicidazolidin-2-HCl-1-yl]-carbonylamino]-4H-nitrophenylanoic acid, D-α-[/3-methylisulphianylicmidazolidin-2-amino]oic acid -ion-1-yl/-carbonylamino]-4-hydroxyphenylaminoic acid, D-α-[/3-methylsulfonylmidazolidin-2-one-1-yl/7-carbonylamino]-thienyl-[2H-otooic acid, D-α-[/3-methylsulfonyliimidiazolidin-2-one-1-yl/Hcarbonylamino]-4-methylsulphions! lofeny0.oo! Otoic acid, D-α-[(3-ethylsulfonyl-imidazalidin-2-one-1-yl)-carbonylamino]-4-chlorophenyl-anoic acid, D-α-[(3-ethylsulfonyl)-1-miidazolidin-2-one-1-yl) /-carbonylamine! o]-4-methylphenylamino]-4-nitrophenylacetic acid, D-[alpha]-[(3-ethylsulfonylimidazolidin-2-one-1-yl) acid (-)carbonylamino]-4-hydroxyphenylacetic acid, D-α-[(3-ethylsulfonyl-2-one-1-yl)-carbanylamino]-(thienyl-[2]-acetic acid. D-α-[(3-ethylsulfonyl]midazolidin-2-yl) -he-1-yl)-carbonylaminio]-4H-methylsulfonylphenyl)-acid, D-α-[[β-acetylcimidazolidin-2-one-1-yl]-carbanylamino]-4-chlorophenylaminoic acid, D-α-[/ -3H-Acetylmidazolidin-2-one-1-yl/-carbonylamino]-4-methylphenylacetic acid, D-α-[/-3-acetylimadazolidin-2-one-1-yl/-carbonylamino]-4-nitrophenylacetic acid, D-α-[/-3-acetylcinide/azolidin-2-one-1-yl/-carbonylamino]-4-hydroxyphenylacetic acid, 1072 18 - bonyitoamino]-4H-dienyl-(12H-acetic acid), D-[alpha]-[[-3-acetylcimidazol]Myn-2Hon-1-yl]-carbcylamino]-4-methylsulfonylphenylacetic acid, D-[alpha]-t[3-formylimlidazolidine] -2-on-l- D-α-[(3-formyl)imlidaziolidin-2-one-1-yl]-carbc"ylamino]-4-me(thiophenylaic acid, D-α-I/3-fomylimiidase EN EN

Claims (1)

1. Claim 1. A process for the preparation of novel penicillins of the general formula (I) wherein R1 is an alkyl radical, an alkoxy or an alkylamino group having 1 to 4 carbon atoms; or a phenyl group, X' is a CO or SO 2 group and B is a thienyl group or a group of formula V wherein R7, R8 and R9 are hydrogen, halogen and/or alkyl groups having 1-5 carbon atoms , and their salts, wherein the compounds (those related to the dissymmetry center Cx may occur in both possible R and S configurations and as a mixture of diastereomers resulting therefrom, characterized in that the 6-aminopenicillanic acid of the formula 2 undergoes reaction with optionally formed in situ reaction product of a compound of general formula 3 where R1, X and B are as defined above, and a compound of general formula 4 wherein R and R13 are such or different dollyl groups containing 1 to 5 carbon atoms and W is a halogen atom, in the presence of a base at -70°C to +50°C, and the resulting penicillins are optionally salted. NN-C0-NH-CH-C0NH-CH2-CH2 ^ M •CH—CH FORMULA 1 0 / CH" COOH ,CH3 -CH, H-N— CH—CH \_. COOH -CH3 CH, 0 -V C 1 R^-N^ ^N-CONH-CH-COOH 1 ¦ \ CH2—CH2 B Formula 2 Formula 389 072 K15 W K13 W O A ChUSO,,— N N-CONH-CH-COOH 3 c \ / Cl Formula 8 NFORM 4 O ^A CH3S02 Nv N-CONH-CH— COOH PATTERN 9 CH3— S02— N N-CO-NH-CH- COOH PATTERN 5 PATTERN 10 S. xCH3 A w _. CH.-S0L-N N-CONH-CH-CONH^-f 0 COONa FORMULA 6 O AND CH,- SOu-N N-CONH-CH-COOH FORMULA 11 O !1 M CH,CO-N' J - CONH- CH-COOH CH3S02- 0 A N N-CONH -CH— COOH (R) FORMULA 7 FORMULA 12 O A olco-n' ^n-co-nh-ch-cooh 3 \ / CL FORMULA 1389 072 A O-LCO-N N -CONH-CH-COOH and! 1 AA H O/A PATTERN. CH,CO-N N-CONH-CH-COOH / FORMULA 15 O A. CHr CO-N' 'N"~ CONH-CH-COOH FORMULA 16 O A Y CH3SO2-N j^-CONH-CH-CONH \/ (R.s ) FORMULA 20 O A CHj- SOL- N N- CONH- CH- CONH 3 £ \ / (5) CH A U, A COOfA A. A FORMULA 21 O ^ CH, I COONa -S. .CH, CH3-Sq-N N-CONH-CH-CONH-j—j^^N/""3 caVcanaV \^ FORMULA 22 COONa O A CH,50--N N —COQ FORMULA 17 O CH3— S02-N NH FORMULA 13 O • CH,SCL- N N-CONH-CH-CONH N (s) S, ,CH, N / , COONa CH3CO-N N-CONH -CH-CONH O FORMULA 23 O O A A CH3—CO-N N-COCl CHsCO — N. NH FORMULA 2A O FORMULA 25 CH CH 3 * CR.S) CH3CO-N N-CONH-CH-CONH-]—[ aa AS, /CH, COONa Cl FORMULA t9 O and CM5 COONa Cl89 073 0 A (RS) CH3CON N-CONH - CH- CONH-r- N.S. /Ch CHO 1 COONa /COx 3 CgH5— S02— N NH EMULA 33 CH, EMULA 27 /C0\ 00 C2H5- S08- N N- CO-NH-CH-CO-NH- r-t^S\/CH3 CH£0—f( N-CONH-CH-C0NH-,—f \ AHJ s o TI ^ o' /Vn O-L COONa CH, COONa FORMULA 3 A FORMULA 28 O A /cox , , C2H3-S02 -N N-CO-NH-CH-CO-NN-p-j^ X y 3 CH3CO-N N-aDW-DH-CC)NHy^\ACH3 Aer ^ CH a FORMULA 29 ClCH, O I v-"3 COONa COONa a FORMULA 35 CH, /C0\ M .& CH3 C^-SOfe-N ^N-CO-NH-CH-CO -NH-r—^ x ' 3 O I "-"3 COONa FORMULA 30 /C0X (D) C.H.—SOfe-N N-CO-NH-CH-COOH CO Cf H5- SOr Ns N-CO- NH-CH- COOH Cl .2n5 0^2 FORMULA 31 /C°\ «S° CgHg— SO2— N • N- C^ Cl FORMULA 32 FORMULA 36 A (R.S) SCHCHgSOjN' 'N-CONH-CH-CONH-i— f \/ 3 COONa ChU O A FORMULA 37 (R.S) CH,S0,—N N-CONH-CH-COOH 3 c \ / 1 CH, FORMULA 3889 072 J\ (RS) «, CH CH3OCONn N-CONH-CH- CONH-p-Y'^ / 3 o' "^ XCH COONa Q FORMULA 39 o o ch3oco-n N-coa cH.oco-r^NH \AZ-7ftR 41 WZ.UK ~iv^ 0 k/ Jk I /S •CH3- CKOCP-N N-CONH-CH-COhWT—f V COONa SAMPLE 42 O A M CH30C0-N N-CONH-CH-COOH S SAMPLE 4389 072 ^-F CH,S0,NX NNC0NH-CH-C0NH l3w»V2l (D,L) rVHj COONa i3ov2r FORMULA 44 ,CH, CH^OaN^NCONH-CH-CONH-, f\/Cn* COONa FORMULA 45 CH-NHS0,K \iCONH-CH-C0NH-, f \/°H3 3 * PL PL PL